Ultrasound stimulation devices and techniques

ABSTRACT

Ultrasound stimulation devices and related techniques are disclosed. An ultrasound transducer for generating ultrasound energy is carried by a transducer housing that seals the transducer and may also include a positioning element for positioning the transducer proximate an application area to which generated ultrasound energy is to be applied. The transducer housing may also carry such components as a battery, a wireless receiver, and a controller. The same housing or a separate sensor housing may include an ultrasound sensor that provides feedback to the ultrasound transducer or its controller, illustratively through a wireless transmitter.

CROSS-REFERENCE TO RELATED APPLICATION

The present patent application is a divisional application of U.S.patent application Ser. No. 11/798,123, filed on May 10, 2007, whichclaims the benefit of U.S. Provisional Patent Application Ser. No.60/799,644, entitled “ULTRASOUND STIMULATION DEVICES”, and filed on May12, 2006, the entire contents of both which are incorporated herein byreference.

FIELD OF THE INVENTION

This invention relates generally to ultrasound stimulation and, inparticular, to devices and techniques for applying ultrasoundstimulation.

BACKGROUND

Biological tissue/bone healing and growth have recently attracted agreat deal of research interest in various medical fields. For example,after traumatic luxation and avulsion injury to teeth, root resorptionbecomes a major concern [1, 2, 3]. A favorable crown to root ratio isimportant to support a tooth and to withstand occlusal forces. Increasedroot resorption is commonly observed during orthodontic tooth movementin humans [4].

In severe resorption, where the teeth crown to root ratio is adverselyaffected, increased teeth mobility is often observed in patients andsplinting of these teeth may be required in some patients [5]. Anotheradverse outcome of teeth root resorption is the increased liabilityfacing orthodontists from malpractice claims [6]. The healing patterngenerally depends on the degree and surface area of the damaged root andon the nature of an inflammatory stimulus [2, 7]. If the root damage issmall, it can be healed by new cementum. However, if the root damage islarge, bone may attach directly onto the root surface resulting inankylosis; thereafter osseous replacement and healing by new cementum isquestionable [8, 9]. Infection can cause progressive inflammatoryresorption that can in turn cause tooth loss in a very short period oftime.

It has been reported that 66% of tooth loss following trauma is due toroot resorption and half of these cases involve a progressive type ofroot resorption [10]. Non-invasive methods for tissue healing includeelectric stimulation [11], pulsed electromagnetic field (PEMF) [12], andlow intensity pulsed ultrasound (LIPUS) [13]. In animal studiesinvolving rabbits, a LIPUS device has been used for bone healing andformation during mandibular distraction osteogenesis [13]. LIPUS hasalso been used to stimulate dental tissue formation and enhance teetheruption [14]. In human studies, a LIPUS device has been used for thehealing of orthodontically-induced teeth root resorption [15] and thiswas supported by other in-vitro studies [23].

Studies show that with suitable pulse durations and power densities,LIPUS pulses are very effective for enhancing dental-tissue healing andfor treating the tooth-shortening problem. A congenital anomaly known asHemifacial microsomia, characterized by an underdeveloped mandible(lower jaw) on one side, has also been treated using a LIPUS device tostimulate bone growth in the deficient side, giving patients a moresymmetric jawline [16].

Although success in using therapeutic ultrasound has been repeatedlydemonstrated, devices that are traditionally used for applyingultrasound to a treatment area are bulky, and require a patient to holdthe device in place during treatment. Control of the intensity ofultrasound applied by these devices also tends to be difficult. Forexample, currently available devices use wired communications, and thepossibility of saliva contacting a wire may cause short circuits andendanger a patient.

SUMMARY OF THE INVENTION

Thus, there remains a need for improved devices and techniques forapplying ultrasound stimulation.

According to an aspect of the invention, a device includes an ultrasoundtransducer operable to generate ultrasound energy, a transducer housingfor carrying the ultrasound transducer, and a transducer positioningelement operable to position the ultrasound transducer proximate anapplication area to which the generated ultrasound energy is to beapplied.

The transducer housing may include a transducer portion for carrying theultrasound transducer, and a positioning portion comprising thetransducer positioning element.

The transducer positioning element may be operable to releasably mountthe transducer housing to a support. The support may be a tooth or otherintra-oral structure, for example.

In some embodiments, the ultrasound transducer comprises a low intensitypulsed ultrasound (LIPUS) transducer.

The device may also include a battery disposed in the transducer housingand operatively coupled to the ultrasound transducer.

The transducer positioning element may include, for example, one of: anelement for attachment to an orthodontic bracket that is fastened to thetooth or other intra-oral structure, and an element for attachment tothe tooth or other intra-oral structure.

A controller is disposed in the transducer housing in some embodimentsand is operatively coupled to the ultrasound transceiver. The controlleris operable to control an intensity of the ultrasound energy generatedby the ultrasound transducer.

The device may also include an ultrasound sensor operable to sense theultrasound energy generated by the ultrasound transducer, and to providea feedback signal to the controller.

A wireless transmitter may be operatively coupled to the ultrasoundsensor, and a wireless receiver disposed in the transducer housing maybe operatively coupled to the controller, in which case the feedbacksignal is transmitted from the ultrasound sensor through the wirelesstransmitter and is received by the controller through the wirelessreceiver. The wireless transmitter and the wireless receiver may be anultra-wideband (UWB) transmitter and a UWB receiver, respectively.

In some embodiments, the device includes a sensor housing for carryingthe ultrasound sensor, and a sensor positioning element operable toposition the sensor proximate a sensing area at which ultrasound energyis to be sensed. The transducer positioning element may comprise thesensor positioning element.

The transducer positioning element and the sensor positioning elementinclude, in some embodiments, a combination selected from a groupconsisting of: the transducer positioning element comprising an elementfor attachment to an orthodontic bracket that is fastened to a tooth orother intra-oral structure, and the sensor positioning elementcomprising a plate structured for retention by a portion of an oralcavity, the transducer positioning element and the sensor positioningelement comprising a tooth crown for attachment to the tooth, thetransducer positioning element and the sensor positioning elementcomprising respective elements for releasably retaining the transducerhousing and the sensor housing at respective portions of a body of apatient proximate the application area and the sensing area, thetransducer positioning element and the sensor positioning elementcomprising an element for releasably retaining both the transducerhousing and the sensor housing at one or more portions of a body of apatient proximate the application area and the sensing area, and thetransducer positioning element and the sensor positioning elementcomprising respective elements for positioning the transducer and thesensor relative to a cell culture.

Such a device may be used, for example, for provision of ultrasoundstimulation to stem cells.

A method of making an ultrasound stimulation device is also provided,and includes providing a transducer housing for carrying an ultrasoundtransducer, providing a transducer positioning element operable toposition the ultrasound transducer proximate an application area towhich ultrasound energy is to be applied, and installing in thetransducer housing an ultrasound transducer operable to generateultrasound energy.

The operation of providing a transducer positioning element may involveforming the transducer positioning element as part of the transducerhousing.

Providing a transducer housing may also or instead involve moulding thetransducer housing.

The method may also include installing a battery in the transducerhousing, and connecting the battery to the ultrasound transducer.

In some embodiments, the method includes installing a controller in thetransducer housing, and connecting the controller to the ultrasoundtransceiver, the controller being operable to control an intensity ofthe ultrasound energy generated by the ultrasound transducer.

The method may further include installing a wireless receiver in thetransducer housing, and connecting the wireless receiver to thecontroller, the wireless receiver being operable to receive a feedbacksignal from an ultrasound sensor and to provide the received feedbacksignal to the controller.

In some embodiments, the method includes providing a sensor housing, andinstalling in the sensor housing the ultrasound sensor and a wirelesstransmitter operatively coupled to the ultrasound sensor.

A device according to another aspect of the invention includes anultrasound sensor operable to sense an intensity of ultrasound energy ata sensing area, the ultrasound energy being generated by an ultrasoundtransducer that is controlled by a controller based on a feedback signalfrom the ultrasound sensor, a wireless transmitter operatively coupledto the ultrasound sensor and operable to transmit the feedback signalfrom the ultrasound sensor to the controller, a sensor housing forcarrying the ultrasound sensor, and a sensor positioning elementoperable to position the ultrasound sensor proximate the sensing area.

The wireless transmitter may be a UWB transmitter, for example.

A self-contained ultrasound stimulation device is also provided, andincludes an ultrasound transducer unit comprising an ultrasoundtransducer operable to generate ultrasound energy, a controlleroperatively coupled to the ultrasound transducer and operable to controlthe ultrasound transducer based on a feedback signal, and a wirelessreceiver operatively coupled to the controller, a transducer housingsealing the ultrasound transducer unit, an ultrasound sensor unitcomprising an ultrasound sensor operable to sense ultrasound energy at asensing area and to generate the feedback signal based on sensedultrasound energy, and a wireless transmitter operatively coupled to theultrasound sensor and operable to transmit the feedback signal to theultrasound transducer unit, and a sensor housing sealing the ultrasoundtransducer.

This type of device may be used, for instance, for stimulation of stemcells in a cell culture located between the ultrasound transducer unitand the ultrasound sensor unit. In one embodiment, such a device is usedfor stimulation of stem cells in a cell culture in which one of theultrasound transducer unit and the ultrasound sensor unit is floated.

Other aspects and features of embodiments of the present invention willbecome apparent to those ordinarily skilled in the art upon review ofthe following description.

BRIEF DESCRIPTION OF THE DRAWINGS

Examples of embodiments of the invention will now be described ingreater detail with reference to the accompanying drawings.

FIG. 1 is a block diagram of a device according to an embodiment of theinvention.

FIGS. 2A and 2B are side and plan views, respectively, illustrating theuse of an intra-oral device of an embodiment of the invention.

FIG. 3 is a side view illustrating the use of an intra-oral device ofanother embodiment of the invention.

FIG. 4 is a schematic diagram of a Complementary Metal OxideSemiconductor (CMOS) oscillator.

FIG. 5 is a block diagram of an ultrasound transducer unit according toa further embodiment of the invention.

FIG. 6 is a plot showing example pulse characteristics for theultrasound transducer unit of FIG. 5.

FIG. 7 is a block diagram of an example ultrasonic signal generator ofthe ultrasound transducer unit of FIG. 5.

FIG. 8 is a schematic diagram of an example ring oscillator circuit thatmay be used as the ring Voltage Controlled Oscillator (VCO) of theultrasonic signal generator of FIG. 7.

FIG. 9 is a schematic diagram of an example power amplifier circuit thatmay be used as the transducer driver of the ultrasound transducer unitof FIG. 7.

FIG. 10 is a front view illustrating the use of a device of anotherembodiment of the invention.

FIG. 11 is a front view illustrating the use of a device of yet anotherembodiment of the invention.

FIG. 12 is a side view illustrating the use of a device of a furtherembodiment of the invention.

FIG. 13 is a side view illustrating the use of a device of anotherembodiment of the invention.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

In some embodiments of the invention, a LIPUS device is miniaturized forintra-oral usage. Specifically, designs according to such embodiments ofthe invention may include any or all of the following aspects:

1) reducing the size of the ultrasound transducer so that it can be usedcomfortably inside a patient's mouth;

2) miniaturized LIPUS devices using wireless connections so that salivafrom patients' mouths will not cause short circuits and thus endangerthe patients;

3) the device and a battery may be packed in biocompatible materials,such that the resulting devices may be mountable onto an orthodonticbracket, or even directly to a tooth using a plastic tooth crown(removable crowns, only for LIPUS application), for example, to avoidthe need for patients to press down on or otherwise hold a transducer inplace to ensure tight contact with gingival tissues;

4) an energy sensor is utilized to evaluate the degree of powerimpedance and the effective LIPUS power that reaches teeth roots withinthe bone, and may be housed behind the palatal bone in an acrylic plate,for instance.

A system-on-a-chip (SoC) solution is one possible implementation of aminiaturized wireless-controlled LIPUS device, which could be used tonon-invasively and safely enhance dental tissue healing and/or tostimulate bone growth, or more generally to provide targeted ultrasonicstimulation.

A miniaturized LIPUS transducer that has a size of about a squarecentimetre could be housed in an intra-oral device that fits comfortablyinside a patient's mouth, although other sizes of transducers and/ordifferent types of transducers may also be suitable for this purpose. Anintra-oral wireless device can be utilized, for example, to preventtooth root material loss and/or to enhance dental tissue healing/bonegrowth or bone supporting teeth loss thus preventing tooth loss.

In some embodiments, an intra-oral device is “smart”, in the sense thatintelligent control may be provided by implementing a feedback controlloop. A wireless feedback control loop might be provided usingultra-wideband (UWB) wireless communication techniques. UWB is arelatively new short-range communication system.

UWB's carrier-less nature provide the advantages of better penetrationand low-power transmission compared to the penetration and transmissionpower of conventional wireless systems. Since UWB signals spread from 0to a few GHz at a very low signal level, they do not cause interferenceto ultrasound transducers. UWB, moreover, is complementary to ultrasoundtissue stimulation.

As noted above, device miniaturization may come from an embedded SoCdesign, by using microfabrication technology. The resulting product(s)can be tailored to varying sizes of teeth or biological tissue which arein need of ultrasound stimulation. Devices according to some embodimentsof the invention as disclosed herein are non-invasive and may be sold,for example, for intra-oral use.

The operating circuit of an ultrasound stimulation may produce a desiredpulse waveform, such as a waveform with a modulation characteristic of“ON” for 200 μs and “OFF” for 800 μs, and output power densities up to30 mW/cm2. The outputs of such a device may match existing OPUS outputsthat produced the significant biological effects mentioned above.

FIG. 1 is a block diagram of a device according to an embodiment of theinvention. It should be appreciated that FIG. 1 represents only oneembodiment of the invention, and that other embodiments may includefurther, fewer, or different components interconnected in a similar ordifferent manner than explicitly shown. For example, although a batteryor other power source might be provided for an ultrasound transducerunit and an ultrasound sensor unit, power sources have not beenexplicitly shown in FIG. 1 so as to avoid overly complicating thedrawing. The contents of the other drawings are similarly illustrativeand do not limit the scope of the present invention.

The device 10 includes an ultrasound transducer unit 11 and anultrasound sensor unit 13, although both units need not be provided inall embodiments. The ultrasound transducer unit 11 may include any ofvarious forms of an ultrasound transducer 19 that is operable togenerate ultrasound energy and components for driving the transducer. Inthe device 10, the ultrasound transducer unit 11 includes a crystaloscillator 12 operatively coupled to a phase detector 14, which isoperatively coupled to a programmable divider 20. The phase detector 14is also operatively coupled to a loop filter 16, which in turn isoperatively coupled to a VCO 18. The VCO 18 is operatively coupled tothe programmable divider 20 and to a demultiplexer (DEMUX) 17. Acontroller circuit 22 is operatively coupled to the programmable divider20 and to a pulse generator 15, which is operatively coupled to theDEMUX 17. The DEMUX 17 provides a drive signal to the ultrasoundtransducer 19 through a buffer 21 in the example shown. The drive signalis based on outputs of the VCO 18 and the pulse generator 15. Thecontroller circuit 22 is also operatively coupled to a wireless receiver23 in the example shown in FIG. 1.

The amplitude and frequency, fout, of the VCO 18 output, and thus thedrive signal provided to the ultrasound transducer 19, may be in therange of 40 kHz and above, for example, and can be tuned by thecontroller circuit 22. The controller circuit 22, also referred to moregenerally herein as a controller, may receive feedback from anultrasound sensor 27 of the ultrasound sensor unit 13 through a wirelesstransmitter 25 and the wireless receiver 23, for instance, and cause theamplitude and frequency of the VCO 18 output and thus the drive signalto vary accordingly. The drive signal is used as the input of theultrasonic transducer 19.

In one design, a CMOS Phase Locked Loop (PLL) is used to implement thephase detector 14, the loop filter 16, the VCO 18, and the programmabledivider 20 shown in FIG. 1. Implementations using other types of devicesare also contemplated. Those skilled in the art will be familiar withPLLs and other possible implementations of the components shown in FIG.1 and their operation.

FIGS. 2A and 2B are side and plan views illustrating the use of anintra-oral device of an embodiment of the invention. The example device30 includes a transducer housing 34, which can be provided in any ofvarious sizes, and a positioning element 36 that can be mounted onto anintra-oral structure such as an individual tooth 40, as shown, toposition an ultrasound transducer carried by the transducer housing 34proximate an application area to which ultrasound energy is to beapplied. The transducer housing 34 carries a miniaturized ultrasoundtransducer, such as a LIPUS transducer. In the example shown, theultrasound transducer is carried inside the transducer housing 34.

The device 30 shown in FIGS. 2A and 2B is designed with a positioningelement 36 in the form of clips or hooks, illustratively stainless steelclips or hooks, to be attached to an orthodontic bracket 38. This typeof positioning element 36 thereby “indirectly” mounts the transducerhousing 34 to a tooth 40. Another possible embodiment of a transducerhousing and a transducer positioning element is a tooth crown, such as aplastic crown. The tooth crown could be removable and only used forLIPUS application. One such device is shown in FIG. 3 and describedbelow.

The relative locations of the positioning element 36 and the transducerhousing 34 are such that the ultrasound transducer carried by thetransducer housing is positioned adjacent or proximate to an applicationarea to which ultrasound energy is to be applied when the transducerhousing is mounted on a tooth. Those skilled in the art will appreciatethat although it may generally be desirable to have the transducerhousing 34 in contact with an application area, some degree ofseparation between an ultrasound transducer and an application area maybe acceptable.

In the example shown in FIGS. 2A and 2B, the application area isgenerally the root 46 above the tooth 40 on which the device 30 is to bemounted, although offset positions are also possible; such as to allowthe device to be mounted to one tooth for application of ultrasoundenergy to a different tooth or portion of a jaw 32.

A shelf, cavity, or any of various other structures may be used in or onthe transceiver housing 34 to carry a transducer and/or possiblyassociated components such as a battery, a controller, and a wirelessreceiver.

The device 30 shown in FIG. 2A also includes a sensor 42 carried by adifferent housing 44, which may be an acrylic plate fabricated fromself-curing acrylic resin, for example. Such a plate can be easilyfabricated from a patient's dental cast, which is a positive replica ofa portion of the patient's oral cavity, specifically the teeth and jaw,so that the plate can be worn by a patient and retained inside themouth. Orthodontic stainless steel clasps or hooks, a friction fit, orsome other arrangement might then be used to retain the plate in place.

In other embodiments, both a transducer and a sensor are positionedusing the same positioning element. Transducer and sensor housings couldbe located relative to the positioning element so that the transducerand sensor are positioned proximate application and sensing areas,generally overlapping each other as shown in FIG. 2A, for example, whenthe housings are mounted on a tooth or other support.

FIG. 3 is a side view illustrating the use of an intra-oral device ofanother embodiment of the invention, wherein the same positioningelement is used for a transducer and a sensor. As shown, the device 50includes a transducer housing 54 carrying an ultrasound transducer, asensor housing 62 carrying a sensor, and a positioning element 56 in theform of a removable crown for mounting the device 50 to a tooth 60. Thedevice 50 may be used to provide ultrasound stimulation to the root 66of the tooth 60, and/or to a different tooth, root or portion of a jaw52.

The transducer housing 54 and/or the sensor housing 62 may be in theform of an acrylic plate that is bonded or otherwise attached to thecrown 56, which may be an acrylic or polycarbonate crown for instance.The housings 54, 62 and the crown 56 could instead be integrated into asingle housing that includes a transducer portion for carrying thetransducer, a sensor portion for carrying the sensor, and a positioningportion for positioning the transducer and the sensor.

The housing(s) for an intra-oral device could be fabricated in any ofvarious ways. Any or all of a positioning element, a transducer housing,and a sensor housing could be milled or otherwise formed in a housing“blank”. Moulding or casting represent examples of other fabricationprocesses. In another possible process, identical copies of the devicesare mass produced and then for each device, its housing(s) can becustomized to the desired shape and size to fit an individual patientusing techniques such as laser machining.

It should also be appreciated that the present invention is in no wayrestricted to a one-piece housing. The bracket clips 36 shown in FIGS.2A and 2B, for example could be provided as separate components andattached to a transducer housing during device manufacture, or possiblylater to provide for adjustment of the relative positions of the clipand the transducer for different mounting and application areageometries. The plate 44 could also be formed around the sensor 42 aftera cast of a patient's teeth and jaw is taken. Similarly, the crown 56could be provided separately from the transducer housing 54 and/or thesensor housing 62, with those housings later being bonded or otherwiseattached to the crown.

Mechanisms for allowing adjustment of the relative positions of atransducer and/or sensor are also possible, to ensure that a transduceris properly located proximate and possibly in contact with anapplication area and that a sensor is properly located to sense energyfrom the transducer, for example.

Designs as shown in FIGS. 2A and 2B and in FIG. 3 eliminate the need fora patient to bite down on or otherwise hold a device for a treatmentperiod, which may be 20 minutes per day in some cases. In oneembodiment, the device parts are housed in acrylic plates of 0.5 mmthickness, although other biocompatible materials might instead be usedto seal parts of the device. These types of housings serve as electricalinsulators to reduce the risk of a patient experiencing a short circuitbetween device components and any filling material within the patient'smouth, for example, or through other liquids or material in differentapplications.

In some embodiments, the dimensions of the transducer are 5-10 mm wide,depending on the size of the patient's tooth or teeth and the size ofthe application area, and 10-15 mm long with 1 mm thickness to fitdifferent tooth-root lengths, for example. The acrylic cover material,which itself may form the housing(s), may also be hard enough towithstand pressure and handling (2-3 psi).

The transducer material may be a thin poly vinylidene fluoride (PVDF)that is commercially available and can be cut to any suitable dimensionsand packed with a miniaturized driving and control circuit and one ormore batteries, illustratively button batteries. This assembly may becovered with an acrylic housing and, for example, either mounted toorthodontic brackets using stainless steel hooks or bonded to acrylic orplastic temporary teeth crowns to hold the transducer in place duringthe LIPUS application. The acrylic or plastic crowns could be very thin(about 0.5-0.25 mm thickness) and thus well tolerated by patientswithout any problem or major adjustments. If adjustments are needed,they can be easily made at the dentist/orthodontist office when theminiaturized device is first prescribed.

For wireless sensor feedback, a high-order monocycle (HOM) UWBmodulation scheme may be used to overcome time jitter problems.Simulation results demonstrate that HOM is more robust than theconventional UWB design using the Rayleigh waveform. Several designshave been presented in transactions and conference proceedings [17, 18,19]. HOM designs, and possibly other schemes, can be used to operativelycouple a sensor with a transducer. A UWB transmitter and receiver canprovide an appropriate feedback channel for controlling the emittedultrasound power level in order to ensure that the ultrasound deviceoperates within an optimum level. A closed loop design may be provided,for example, using two chips, including one for the transducer and theother for energy sensing.

Major orthodontic and endodontic materials supply companies are activelylooking for solutions to enhance dental-tissue and bone growthstimulation and healing. Devices according to embodiments of theinvention can potentially provide safe and low-cost treatment fortooth-root fracture and tooth-root resorption, and can be easily adaptedfor industrial use. In addition to many applications for dental care,the device can also be modified for other tissue growth stimulationhealing. For example, in Hemifacial Microsomia, or underdevelopedmandible, a device as disclosed herein can be used to stimulate bonegrowth in the deficient side, giving patients a more symmetric jawline.

Embodiments of the invention have been described above primarily in thecontext of physical structures and features. However, internal designaspects of intra-oral ultrasound devices have also been considered.

Currently, several prospective implementation techniques exist. Forexample, one can use an inductance-capacitance VCO or a ring oscillator.An advantage of the first design is that the resulting circuit has lowphase noise, but it also has limited tunable frequency range and isdifficult to implement in silicon. The ring oscillator design has awider tuning range and is easy to implement. For a 40 kHz and highertuning range, a ring oscillator approach may be preferred.

An example ring oscillator design is shown in FIG. 4. The CMOS ringoscillator 90 includes transmission gates 92, 98, 104, which areinterconnected to provide positive feedback in order to satisfyBarkhausen's criteria (gain>1, phase difference=360°). In this CMOSoscillator 90, transistors 94, 96, 100, 102, 106, 108 are operativelycoupled between VDD and ground potential, and transmission gates 92, 98,104 are operatively coupled between VDD−Vctrl1 and Vctrl2. Theoscillation frequencies are varied by Vctrl1 and Vctrl2, which controlthe effective resistance of the transmission gates 92, 98, 104.

UWB signals and LIPUS are complementary in some embodiments, with UWBbeing for wireless control, and LIPUS being for ultrasound stimulation.A LIPUS device may work at 1.5 MHz while UWB can spread from 0 to GHzfrequency, for instance. Ultrasound stimulation can potentially beapplied to various application areas simultaneously by networkingmultiple transducers and their associated UWB transmitters together. Atime-hopping binary symbol emitted by the UWB transmitter at the s_(tr)^((k))(u,t), in time-hopping high-order modulation (HOM) can be writtenas

${{s_{tr}^{(k)}( {u,t} )} = {\sum\limits_{j = 0}^{N_{s} - 1}{( {1 - {2{D^{(k)}(u)}}} ) \cdot {\omega_{tr}( {t - {jT}_{f} - {{c_{j}^{(k)}(u)}T_{c}}} )}}}},$

whereD^((k))(u)ε{0,1} is a transmitted symbol bit from the kth tooth's UWBtransmitter;N_(s) impulses are employed per symbol bit in time-hopping UWBmodulation;t is the transmitter's clock time;ωtr( . . . ) represents a transmitted impulse waveform function or amonocycle;u indicates a point in an underlying probability sample space;c_(j) ^((k))(u) is a pseudo-random time-hopping pattern of the kthtransmitter introduced to avoid symbols from various UWB transmitterscolliding with each other in a multi-access environment;T_(c) is chip duration.

A device as shown in FIGS. 2A and 2B and in FIG. 3 may include anultrasound generator and a UWB receiver in a transducer housing 34, 54,and an ultrasound energy detector and a UWB transmitter in a sensorhousing 44, 62. One example of an ultrasound generator has beendiscussed previously. With respect to UWB transmitter design, oneembodiment uses a microcontroller coupled with a fast digital to analogconverter (DAC) to generate desired UWB monocycles. The UWB waveformscould be stored in memory and read out when needed. The output power atthe ultrasound transducer can be adjusted automatically based on theenergy sensor's power measurement to achieve optimum output powerintensity, illustratively 30 mW/cm2 at the transducer's surface. Thevalue of 30 mW/cm2 is based on previous research that examined theeffects of pulsed ultrasound on animal models at different powerintensities [22]. The available output power is limited to a maximumvalue in some embodiments in order to prevent overheating dental orother tissues.

With respect to the UWB receiver design, the receiver may decode areceived symbol based on decision statistics, θ_(j)=∫r(u,t−t_(j))υ(t)dt,assuming perfect knowledge about the channel. In this decisionstatistics expression, t_(j) represents asynchronization caused bytiming jitter and other channel impairments, and θ_(j) is thecorrelation between the received signals

${r( {u,t} )} = {{\sum\limits_{k = 1}^{N_{u}}{A_{k}{s_{rec}^{(k)}( {t - {\tau^{(k)}(u)}} )}}} + {n( {u,t} )}}$

and template waveforms

ν(t)=ω_(rec)(t−jT _(f) −c _(j) ^((l)) T _(c)−τ_((l)),

whereT_(f) is a time-window in which each individual pulse can move around;T_(c) is the pulse position with reference to the boundary of T_(f);A_(k) is the gain of the kth transmitter;τ^((k))(u) is a random variable representing the time asynchronism; and)n(u,t) represents Gaussian thermal noise.

The energy detector can be designed, for example, to measure only thepower spectrum density for the signal in the frequency range above 40kHz. The transducer and the energy sensor work together. If thetransducer does not generate ultrasound, the energy sensor may informthe patient that the device is not working, by generating an audiblesignal for instance. If the power level is too low, the energy sensorfeeds back to the transducer to increase the energy level, if possible,without exceeding a limit, illustratively 30 mW/cm2.

In some embodiments, the transducer and the energy sensor are powered bybuilt-in button batteries, many of which are commercially available fromvarious manufacturers. The transducer, in one particular implementation,needs a current of 20 mA and a supply voltage of 1.5V. A 540 mAhbattery, for example, can be expected to last 27 hours (540 mAh/20 mA)in this implementation, which exceeds a normal course of ultrasoundstimulation of 20 minutes/day for four weeks. A device housing,batteries, or both could be customized depending on a desired overallsize of an ultrasound device.

In one embodiment, LIPUS is used at 1.5 MHz with pulse repetition rateof 1.0 kHz, the pulse duty cycle is 20% (i.e., a ‘pulse’ duration of 200μs and a ‘null’ duration for 800 μs), and the average intensity of thepulsed ultrasound is approximately 30 mW/cm2. These characteristics maybe exhibited, for example, using a piezoelectric transducer with aresistance of approximately 5Ω at 1.5 MHz frequency. Piezoelectrictransducers of different characteristics can be accommodated afteradjusting the signal amplitude to ensure desired ultrasound intensity,for example.

For one particular transducer having a contact area of approximately 2cm2, a pulsed ultrasound with an average power of 60 mW is used. Sincethe duty cycle in this example is 20%, the average signal power duringthe ‘pulse’ phase is 300 mW. This implies a root-mean-squared (RMS)voltage amplitude of approximately 3.87Vrms. However, a considerablyhigher voltage may be applied. A higher voltage might be used, forinstance, to compensate losses incurred due to imperfect conversionefficiency from electrical to mechanical (ultrasound) energy and/or forimperfect ultrasound transmission from the transducer to tissues to bestimulated.

According to one embodiment, ultrasound energy is generated with anintensity of approximately 850 mW, corresponding to a square wave withpeak amplitude 13Vp during the ‘pulse’ period. A transducer unit havingincreased portability and relatively small size may be provided using a3V battery, illustratively a Lithium Iodide battery such as used in pacemakers, as a power source. To generate the above-noted 13Vp square wave,a larger supply voltage may be generated using a DC-DC converter.

FIG. 5 is a block diagram of one such ultrasound transducer unitaccording to a further embodiment of the invention. The example unit 110includes a 3V battery 112 as a power source, a DC-DC converter 114operatively coupled to the battery 112, an ultrasonic signal generator116 operatively coupled to the battery, to the DC-DC converter and to apiezoelectric transducer 119.

Various forms of DC-DC converters suitable for use as the DC-DCconverter 114 will be apparent to those skilled in the art. Thoseskilled in the art will also be familiar with piezoelectric transducerssuch as 119. It should be appreciated, however, that not all embodimentswill necessarily employ a DC-DC converter, and that other types ofultrasound transducer than a piezoelectric transducer may be used. Oneexample implementation of the ultrasonic signal generator 116 is shownin FIG. 7 and described below, although other designs may also bepossible.

In the ultrasound transducer unit 110, the frequency of an ultrasonicsignal generated by the piezoelectric transducer 119 can be adjusted bytuning voltages the Vp and Vn input to the ultrasonic signal generator116. The input pins “Pulse width input” and “Null width input”,represented in a binary format in FIG. 5 as

p1 p2 p3 p4 p5 p6 p7 p8 p9 p10 p11 p12; and

p13 p14 p15 p16 p17 p18 p19 p20 p21 p22 p23 p24, are used to set thepulse repetition rate and duty cycle of resulting final waveform Voutf.In some embodiments, p1, p13 are the least significant bits (LSBs) inthese inputs, and p12, p24 are the most significant bits (MSBs).

The “Null Width Input” may specify the length of a null period, as anumber of clock cycles for instance, whereas “Pulse Width Input” sets apulse duration, illustratively as a number of clock cycles during whichthe pulse is on. For example, setting “Null Width Input” to0100101100002 (=120010) and “Pulse Width Input” to 0001001011002(=30010) produces the pulse characteristics shown in the plot of FIG. 6.

FIG. 7 is a block diagram of an example ultrasonic signal generator ofthe ultrasound transducer unit of FIG. 5. The example generator 116includes a ring VCO 118, a transducer driver 120, which is an amplifier,operatively coupled to the ring VCO, a counter 134, a comparator 136operatively coupled to the ring VCO through two inverters 122, 124 andto the counter, two tristate buffers 138, 140 operatively coupled to thecomparator, and a JK flip-flop 144 operatively coupled to thecomparator, to the tristate buffers, and to the transducer driver. Asshown, an output of the comparator 136 is operatively coupled to a resetinput of the counter 134 through an inverter 148 and an AND gate 146 andto a clock (CLK) input of the JK flip-flop 144, and the Q output of theJK flip-flop is operatively coupled through an inverter 132 to its Jinput. The output of the inverter 132 is also operatively coupled to theK input of the JK flip-flop 144 through an inverter 142, to an enableinput of the tristate buffer 140, to an enable input of the tristatebuffer 138 through an inverter 130, and to the transducer driver 120through another inverter 128 and an AND gate 126.

Various implementations of ring VCOs, amplifiers, counters, comparators,tristate buffers, JK flip-flops, inverters, and AND gates may becommercially available and/or may be apparent to those skilled in theart, and the present invention is not limited to any particularimplementations of these components. Thus, the following functionaldescription of these components will enable those skilled in the art toimplement embodiments of the invention in any of multiple ways.

The ring VCO 118 is used to generate clock signals at 1.5 MHz for theentire ultrasonic signal generator 116. This same clock signal is fed tothe transducer driver 120 to be amplified. The transducer driver 120amplifies 3V digital signals to a higher voltage, illustratively 13V,ultrasound signal that drives the piezoelectric transducer 119 (FIG. 5).A pulsed signal programmed to 1.0 kHz, 20% duty cycle is used in oneembodiment to modulate the ultrasound signals, thus producing desiredpulsed ultrasound.

As discussed above, the “Pulse Width Input” and “Null Width Input” pinsare used to program the ‘pulse’ width and ‘null’ width of a LIPUSsignal. These inputs are fed into the ultrasonic signal generator 116via the tristate buffers 138, 140. The two tristate buffers 138, 140 arealternately triggered into ‘active’ or ‘high impedance’ mode in acomplementary fashion. During every clock cycle, only one of thetristate buffers 138, 140 is activated. The input state of the ‘active’tristate buffer 138, 140 is transmitted to one set of input pins of thecomparator 136 for comparison with the output of the counter 134.

The counter 134, on the other hand, keeps incrementing its count untilits value matches that of the “Pulse Width Input” or “Null Width Input”.At the moment when a match is detected, the comparator 136 asserts its‘Equal’ pin ‘high’, which resets the counter 134 and toggles the JKFlip-flop 144. This brings about a change of phase from the ‘null’ to‘pulse’ or vice versa. The ultrasonic signal generator 116 can beasynchronously reset by de-asserting the System Reset pin.

Illustrative examples of some of the components shown in FIG. 7 aredescribed below, with reference to FIGS. 8 and 9.

FIG. 8 is a schematic diagram of an example ring oscillator circuit thatmay be used as the ring VCO 118 of the ultrasonic signal generator ofFIG. 7. The example ring VCO 118 includes transistors 150, 152, 158,160, 166, 168, 174, 176 operatively coupled between Vdd and ground,transmission gates 156, 164, 172 operatively coupled between transistorpairs and between Vp and Vn, and capacitors 154, 162, 170 operativelycoupled between the transistor pairs, transmission gates, and ground.

As noted above, the ring oscillator 116 provides the clock (CLK) signalfor the ultrasonic signal generator 116 (FIG. 7). A ring oscillator maybe preferred in some embodiments for its capability for generatingrelatively low frequency and for its tunability. In one embodiment, thecapacitors 154, 162, 170 have values of C1=3.7 pF, and are used in eachstage of the ring oscillator 116 to further reduce the oscillatingfrequency to that of a few MHz. In this example, the oscillationfrequency of the CLK signal equals 1.5 MHz when Vp and Vn are set to0.7V and 2.3V respectively.

FIG. 9 is a schematic diagram of an example power amplifier circuit thatmay be used as the transducer driver 120 of the ultrasound transducerunit of FIG. 7. The example power amplifier 180 includes an AND gate 182and a level shifter 184 operatively coupled to the AND gate. The levelshifter 184 includes transistors 186, 188, 190, 192 operatively coupledbetween Vpp and ground, with the control terminals, gate terminals inthis example, of the transistors 188, 192 operatively coupled to theoutput of the AND gate 182. The gate terminal of the transistor 192 isoperatively coupled to the output of the AND gate 182 through aninverter 194.

As noted above, the transducer driver 120 (FIG. 7) amplifies a voltagesignal so as to drive a piezoelectric transducer. The first stage of theamplifier 180, which may be used as the transducer 120, includes the ANDgate 182 acting as a modulator. The AND gate 182 modulates a 1.5 MHzdigital signal with a 1.0 kHz, 20% duty-cycled pulsed signal in oneembodiment. The remainder of the amplifier 180 is a level-shifter thatamplifies a 3V pulsed signal to a higher peak level, such as 13V in anexample described above.

High voltage (HV) n-channel Metal Oxide Semiconductor (NMOS) transistorsand p-channel Metal Oxide Semiconductor (PMOS) transistors are used inthe level-shifter 184 in the example shown. In one embodiment, thesetransistors 186, 188, 190, 192 are capable of withstanding high drain tosource voltage VDS. In the case of a resonant transducer resistance of5Ω, a substantial driving current of magnitude up to 260 mA is expected.In order to satisfy this current driving capability, a number oftransistors are used in parallel but for simplicity, each of theseparallel combinations are represented by one transistor symbol in FIG.9.

An implementation of the design shown in FIGS. 5 to 9 using 0.8 μmCMOS/DMOS High-Voltage process technology has been simulated. With anultrasonic signal frequency of 1.49 MHz, pulse repetition frequency of1.0 kHz, and pulse width of 200 μs, an output signal having 13V peakmagnitude was observed. The average power consumption of the ultrasoundtransducer unit was 225 mW, out of which 170 mW will be delivered to thepiezoelectric transducer 119.

What has been described is merely illustrative of the application ofprinciples of embodiments of the invention. Other arrangements andmethods can be implemented by those skilled in the art without departingfrom the scope of the present invention.

For example, a single device could incorporate multiple transducersand/or sensors. In a case where a patient has root resorption and/orroot fracture from both outside and from inside for instance, then botha labial (outside) assembly and a lingual (inside) assemblies mightcontain respective LIPUS transducers, and possibly respective sensors,transmitters, and receivers.

In addition, devices according to further embodiments might also includeother components than those specifically shown in the drawings anddescribed above. Control parameters for an intra-oral device could bespecified by a user through an interface other than a wirelesstransceiver for instance. Another variation would be to adapt thehousing(s) for mounting to an intra-oral structure such as a bone ortissue other than a tooth.

Regarding the mounting of housings, or more generally the positioning ofa transducer and a sensor, further options are also contemplated. FIG.10 is a front view illustrating the use of a device of anotherembodiment of the invention. In the arrangement shown in FIG. 10, adevice 200 is used for stimulating growth of a jaw. The device 200itself includes an ultrasound transducer, and possibly a UWB receiver,in a transducer housing 214 that is positioned proximate an applicationarea of the jaw, such as just in front of the ear, using a positioningelement. A rubber suction cup 210 is shown as an example of a suitablepositioning element that may be used to removably mount the transducerhousing 214 to the outside of a cheek 212 of a patient. Ultrasound gelmay also be used to improve contact between the transducer housing 214and the skin covering the jaw joint (in front of the ear). Thetransducer housing 214 might be further stabilized in place using a headapparatus (not shown) to apply pressure and hold the transducer housing214 in place.

An ultrasound sensor unit including an ultrasound sensor and a UWBtransmitter is also provided in the sensor housing 204 in the exampleshown. A sensor positioning element in the faun of a crown 206 could beheld on the upper last molar 208 in the side to be stimulated.

Variations of the device 200 may be or become apparent to those skilledin the art. Other positioning elements may be used instead of or inaddition to the suction cup 210 and/or the crown 206, for instance. Thepositions of the transducer housing 214 and the sensor housing 204 couldalso be different than shown in FIG. 10, such as where the inside of thejaw is to be stimulated. In other embodiments, the transducer housing214 or the sensor 204 could be mounted outside the cheek 212 instead ofbetween the cheek and the jaw, as shown in FIG. 11. In this case, both atransducer and a sensor are enclosed in the same housing 213, which ispositioned on the cheek 212 of a patient using the same positioningelement, a suction cup 210 in the example shown. This example alsoillustrates the fact that the same housing and positioning element maybe used for a transducer and a sensor, in which case feedback from thesensor to the transducer might not be provided through a UWB link orother wireless link.

Further variations are also possible.

FIG. 12 is a side view illustrating the use of a device of a furtherembodiment of the invention, and illustrates more generally the use ofan ultrasound device to stimulate an application area and to senseultrasound energy at a sensing area. A transducer housing 230 and asensor housing 224, which respectively carry a transducer and receiverand a sensor and transmitter in some embodiments, may be positioned atportions of a body 222 of a patient. The respective positions of thetransducer housing 230 and the sensor housing 224 are proximate anapplication area to which ultrasound energy is to be applied and asensing area at which ultrasound energy is to be detected.

Such positioning of a transducer and a sensor may be accomplished usingany of various forms of positioning elements. For stimulation of longbone growth, for example, a transducer/UWB receiver could be positionedon top of an epiphysial plate to be stimulated, while a sensor/UWBtransmitter assembly is stabilized on the other side of the stimulatedjoint. The transceiver housing 230 and the sensor housing 224 in thistype of arrangement could be held in place using a temporary adhesive,hook and loop fastener on a garment, etc. This is shown generally inFIG. 12 at 226, 232. Another possible option would be to retain bothhousings 224, 230 on opposite sides of an application area using a beltor strap, as shown at 228.

FIG. 13 is a side view illustrating the use of a device of anotherembodiment of the invention, which may be suitable for stimulatingtissue or cells such as stem cells in a cell culture. The device 240 inthis example includes two sealed units. A transducer unit 244 includesat least an ultrasound transducer, and possibly other components such asa controller and a wireless receiver. The transducer housing 242 sealsthe transducer unit 244. A sensor unit 248 similarly includes a sensorand a wireless transmitter, and is sealed inside the housing 249.Ultrasound stimulation can thereby be applied to a cell culture locatedbetween the ultrasound transducer unit 244 and the ultrasound sensorunit 248, in a cell or tissue culture dish 246 in the example shown. Forexample, the ultrasound transducer unit 244 might be floated in theculture medium of the cell culture.

In order to evaluate the stimulatory effect of LIPUS on cellularactivity, freshly isolated rat bone marrow stem cells were experimentedusing a prototype LIPUS device. These cells were allowed to self-expandand after two weeks, cell counts and alkaline phosphatase measurementswere performed. Comparisons between the cell counts of a control, anultrasound treated group, and the original group illustrated thatapplication of ultrasound stimulation increased stem cell expansion.

The application of ultrasound was also found to stimulate stem cellactivity by increasing alkaline phosphatase expression. Three groupswere used in the experiment: the original group before applyingultrasound, the control group that did not receive ultrasoundapplication, and the ultrasound group that received ultrasoundapplication for 20 minutes per day for 10 days.

Ultrasound transducers were securely attached under a flask containingthe bone marrow stem cells. The experiment demonstrated that applicationof ultrasound is capable of stimulating cellular activity of bone marrowstem cells, in the form of increasing their replication (as indicated bythe increased cell count) and increasing the alkaline phosphataseexcretion.

To study the effect of ultrasound on cellular differentiation, theexpression of Nucleostemin, a specific marker for bone marrow stemcells, was evaluated by Polymerase chain Reaction (PCR). It was seenthat ultrasound stimulation up-regulated the expression of Nucleosteminwhen the bone marrow stem cells were cultured in a basic medium(Dulbecco's Modified Eagle Medium (DMEM), Hank's Balanced Salt Solution(HBSS; without phenol red), penicillin (10,000 U/mL solution),streptomycin (10,000 ug/mL solution), and heatinactivated fetal bovineserum (FBS)). When the bone marrow stem cells were induced to bedifferentiated into osteogenic lineage using osteogenic medium(supplemented with 100 nM dexamethasone, 10 mM glycerophosphate, and0.05 mM ascorbic acid-2-phosphate), Nucleostemin was down-regulated. Itwas further down-regulated when ultrasound was applied. These resultsindicate that a LIPUS device can enhance stem cell differentiation intoboneforming cell lineage.

It should thus be appreciated in view of the foregoing that embodimentsof the invention need not necessarily be restricted to intra-oraldevices. Ultrasound can be used to stimulate stem cell growth/expansion,for example. When culturing cells in vitro, an ultrasound transduceraccording to an embodiment of the invention, which is sterile,disposable, and emits controlled levels of ultrasound, could be providedin a culture flask for promotion of stem cell growth. Such a device maybe implemented as a self-contained ultrasound stimulation device thatincludes an ultrasound transducer for generating ultrasound energy, anda housing sealing the ultrasound transducer.

Although described above primarily in the context of a device, theinvention may be embodied in other forms, illustratively as a method ofmaking such a device. In one embodiment, a method of making anultrasound stimulation device involves providing a transducer housingfor carrying an ultrasound transducer, providing a transducerpositioning element operable to position the ultrasound transducerproximate an application area to which ultrasound energy is to beapplied, and installing in the transducer housing an ultrasoundtransducer operable to generate ultrasound energy. Variations of such amethod, including different ways of performing these operations, andfurther operations that may be performed in some embodiments, are alsocontemplated. Additional operations may include, for instance,installing other components in the transducer housing and/or in adifferent housing and interconnecting installed components.

Further variations of the specific examples disclosed herein are alsopossible. For example, an acoustic mirror could be provided in atransducer unit, on a transducer housing, or possibly as a separateelement to reflect generated ultrasound toward an application area. Anultrasound mirror or reflector might be fabricated on a glass substratewith air micro-cavities inserted, for instance. Masks andphotolithography (photoresist spinner, oven and mask exposure) could beused to define a pattern to be etched, using wet or dry etching, fromthe glass substrate. An ultrasonic transducer and such a reflector maythen be bonded, using wafer bonding techniques for instance. A waferbonding technique might be appropriate where the transducer isfabricated by depositing or sputtering electrodes (e.g., Al, Ag, Au orTi) onto a high-efficiency piezoelectric material, such as PZT orcopolyester.

The use of a high power-density piezoelectric transformer to drive apiezoelectric transducer is also contemplated.

An acoustic mirror and/or a piezoelectric transformer would decreasepower usage and save battery life.

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1. A device comprising: (a) an ultrasound sensor operable to sense anintensity of ultrasound energy at a sensing area, the ultrasound energybeing generated by an ultrasound transducer that is controlled by acontroller based on a feedback signal from the ultrasound sensor; (b) awireless transmitter operatively coupled to the ultrasound sensor andoperable to transmit the feedback signal from the ultrasound sensor tothe controller; (c) a sensor housing for carrying the ultrasound sensor;and (d) a sensor positioning element operable to position the ultrasoundsensor proximate the sensing area.
 2. A self-contained ultrasoundstimulation device comprising: (a) an ultrasound transducer unitcomprising an ultrasound transducer operable to generate ultrasoundenergy, a controller operatively coupled to the ultrasound transducerand operable to control the ultrasound transducer based on a feedbacksignal, and a wireless receiver operatively coupled to the controller;(b) a transducer housing sealing the ultrasound transducer unit; (c) anultrasound sensor unit comprising an ultrasound sensor operable to senseultrasound energy at a sensing area and to generate the feedback signalbased on sensed ultrasound energy, and a wireless transmitteroperatively coupled to the ultrasound sensor and operable to transmitthe feedback signal to the ultrasound transducer unit; and (d) a sensorhousing sealing the ultrasound transducer.
 3. A method of stimulatinggrowth of tissue or cells, comprising the step of applying ultrasoundenergy to the tissue or cells using a device as claimed in claim 1 orclaim 2, wherein the ultrasound transducer generates ultrasound energyhaving an intensity which is adjustable in accordance with a feedbacksignal generated by the ultrasound sensor.
 4. The method of claim 3wherein the cells comprise stem cells in a cell culture.
 5. The methodof claim 4 wherein the cell culture is located between the ultrasoundtransducer unit and the ultrasound sensor unit.
 6. The method of claim 4wherein the cell culture comprises a liquid media.
 7. The method ofclaim 6 wherein one or both of the ultrasound transducer unit and theultrasound sensor unit is floated in the liquid media.
 8. The method ofclaim 3 wherein the ultrasound transducer comprises a low intensitypulsed ultrasound (LIPUS) transducer.
 9. The method of claim 3 whereinthe device of claim 2 further comprises a battery disposed in thetransducer housing and operatively coupled to the ultrasound transducer.